Able to lock onto a key protein on the surface of some breast cancer cells, the drug
trastuzumab (Herceptin) heralded a new generation of "targeted" therapies when it
received federal approval in 1998. Unfortunately, cancer is often a moving target.
In about 20 percent of breast cancer cases, the tumor cells
have an oversupply of a protein called HER2. For women
with such "HER2-positive" tumors, trastuzumab can literally
be a lifesaver. By binding to HER2, the drug prevents it
from transmitting growth signals into the cell, slowing or
reversing tumor growth. Combined with chemotherapy, the
drug shrinks or controls tumors in 75-80 percent of women
with HER2-positive metastatic breast cancer.
Even in these patients, however, the benefits of trastuzumab
are far from permanent. Patients with the most advanced
disease generally have a 10- to 14-month period in which
their condition improves or stays stable, after which it begins
to worsen, although some patients do well for many years.
"It's as though HER2-positive cancers are speeding down
a highway. Trastuzumab cuts them off for a while, but the
tumors have a way of finding off-ramps that enable them to get
around the blockade," says Eric Winer, MD, director of the
Breast Oncology Center within Dana-Farber's Women's Cancers
Program (WCP). "There's a growing scientific and clinical
consensus that even when the cancer progresses, Herceptin is
still providing a benefit, so the drug resistance is only partial.
"We're beginning to understand what's taking place at a
molecular level to enable these tumors to escape the full effect
of the drug," he continues. "What's exciting is that there are
a host of drugs in preliminary clinical trials that appear to
have very clear activity against Herceptin-resistant cancers."
(See A project to bank on.)
Scientists have discovered that when HER2-positive
breast cancer cells become resistant to trastuzumab, proteins
called PI3 kinases become activated within the cells. The
kinases are a family of enzymes – proteins that spark chemical
reactions – first studied by Thomas Roberts, PhD, co-chair
of Dana-Farber's Department of Cancer Biology, and Lewis
Cantley, PhD, of Beth Israel Deaconess Medical Center and
a member of the Dana-Farber/Harvard Cancer Center.
The PI3 kinases usually take their cues from the HER2
protein. HER2 is a "receptor" that juts from the cell surface
like a catcher's mitt waiting for a growth molecule. The "grow"
command is passed along a chain of proteins, including PI3
kinases, to the cell's central command. When HER2 is shut
down by trastuzumab, abnormal PI3 kinases can sometimes
get activated, transmitting growth signals on their own. The
result, in a tumor, is a resurgence of cell division.
Dr. Roberts and his colleague Jean Zhao, PhD, have
developed colonies of HER2-positive cells whose growth
is hobbled by trastuzumab. When they inserted a defective,
or mutated, version of a PI3 kinase, the cells became
trastuzumab-resistant. "Mutations to PI3 kinases may explain
why some patients with HER2-positive cancers don't respond
to trastuzumab, and why patients who initially respond to
the drug eventually relapse," Dr. Roberts comments.
The discovery suggests that some patients could benefit
from drugs that block PI3 kinases. Dana-Farber's Geoffrey
Shapiro, MD, PhD, is leading a clinical trial of such drugs;
the second round of trials will test the drugs specifically in
trastuzumab-resistant breast cancers.
The PI3 kinases aren't the only
proteins in the HER2 pathway that have
attracted scientists' interest. Among
those at the tail end of the route is the
protein NF-kß, which revs up cell
growth and pushes it past all internal
stop signs. A cell with a blocked HER2
receptor but an active NF-kß molecule
will divide as many times as it can.
Because it acts almost directly on the
cell's reproductive machinery, NF-kß
is suspected as a cause of "global resistance,"
in which breast cancers fail to
respond to any current therapy.
"We're using laboratory cell lines
to test whether 'core agents' like NF-kß
are responsible for multi-drug resistance,
either by mutating or being
activated improperly," says WCP
Director J. Dirk Iglehart, MD, who
is pursuing the research with Debajit
Biswas, DSc. Several compounds
have been developed that target key
components of the NF-kß pathway,
including the drug Velcade that has
seen success in treating multiple
myeloma. Further research by WCP
investigators promises to reveal much
about the basic elements of resistance
and lay the groundwork for future
2009 Turning Point
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